LAUSR

BACKGROUND WHO recommends a one- or two-dose human papillomavirus (HPV) vaccination schedule for females aged nine to twenty years. Studies confirming the efficacy of a single dose and of vaccine modifications are needed but randomized controlled trials (RCTs) are costly and face logistical and ethical challenges. We propose a resource-efficient single-arm trial design that uses untargeted and unaffected HPV types as controls. METHODS We estimated HPV vaccine efficacy (VE) from a single arm by comparing two ratios: the ratio of the rate of persistent incident infection with vaccine-targeted and cross-protected types (HPV16/18/31/33/45) to vaccine-unaffected HPV types (HPV35/39/51/52/56/58/59/66) versus the ratio of prevalences of these types at the time of trial enrollment. We compare VE estimates using only data from the bivalent HPV16/18 vaccine arm of the Costa Rica Vaccine Trial to published VE estimates that used both the vaccine and control arms. RESULTS Our single-arm approach among 3,727 women yielded VE estimates for persistent HPV16/18 infections similar to published two-arm estimates from the trial (according-to-protocol cohort: 91.0% (95% CI = 82.9%-95.3%) [single-arm] vs. 90.9% (95% CI: 82.0%-95.9%) [two arm]; intention-to-treat cohort: 41.7% (95% CI = 32.4%-49.8%) [single-arm] vs. 49.0% (95% CI = 38.1%-58.1%) [two-arm]). VE estimates were also similar in analytic sub-groups (number of doses received; baseline HPV serology status). CONCLUSION We demonstrate that a single-arm design yields valid VE estimates with similar precision to an RCT. Single-arm studies can reduce the sample size and costs of future HPV vaccine trials while avoiding concerns related to unvaccinated control groups. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00128661.